This NIMH Research Scientist Development Award II renewal represents commitment to studying the influence of biological rhythm systems of human affective disorders. Clinical features of depression such as its seasonality and its association with early awakening suggest that biological rhythm disorders play a part in depressive illnesses. There are at least two sets of circadian (about 24-hour) rhythms in the human body. A convergence of evidence indicates that the phases of one set of rhythms are advanced in depressed patients, that is, these rhythms peak too early. This rhythm disorder could lead to depressive phenomena by triggering responses analogous to the photoperiodic responses of animals. Antidepressant drugs such as lithium might correct these pathologic responses by slowing or delaying circadian rhythms. Three clinical studies will be done to test these hypotheses, comprising 1) a descriptive study of rhythms in manic and depressed patients, 2) a replication of experimental treatments of depression which shift the time of sleep, and 3) study of depressed patients and controls placed on a 2-hour sleep/wake schedule. These clinical studies will utilize 24-hour monitoring of activity, sleep/wake, core body temperature, urinary potassium excretion, and mood. Three animal models will be created to explore interactions of circadian rhythms with behavioral phenomena. Finally, two laboratory studies will be done to explore relationships of the human REM-nonREM rhythm to circadian phenomena, and an epidemiologic survey will study the depressive phenomena caused by clinical sleep disorders.